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Using tramadol to monitor hepatic drug metabolism in the critically ill
Critical Care volume 16, Article number: P343 (2012)
Previously, we have demonstrated significant inhibition of hepatic drug metabolism by the enzymes cytochrome P450 (CYP) 3A4 and 3A5 in acute kidney injury (AKI) using midazolam as a probe drug [1, 2]. We are now developing the use of tramadol as a probe drug to test the hypothesis that CYP2D6 function is also inhibited by AKI in critical illness. In this study we sought to determine whether a single timepoint tramadol concentration could be identified as a reliable surrogate for measurement of a full area under the concentration time curve after intravenous administration in adults.
We conducted a study of 10 critically ill patients in our hospital's general critical care unit. Tramadol 10 mg was given intravenously, and serum was taken at 0.5, 1, 2, 3, 4 and 8 hours for determination of concentrations of tramadol ([tramadol]) and its two main metabolites. Inclusion criteria: age >18 years, predicted ICU stay >48 hours. Exclusion criteria: recent receipt of tramadol or major CYP2D6 inhibitors, hepatic failure, pregnancy/breastfeeding.
There was a strong correlation between the area under the curve (AUC) of the [tramadol]-time graph and t = 4 hours [tramadol], P < 0.0001, r = 0.983. See Figure 1. The [tramadol] at other timepoints correlated less strongly with the AUC. The mean [tramadol] at 4 hours was 29.7 ng/ml (24.3 to 35.1) and the mean AUC was 257 ng/hour/ml (211 to 303). Analysis of tramadol metabolites confirmed that CYP2D6 was predominantly responsible for tramadol metabolism.
A single blood sample, taken 4 hours post-intravenous tramadol injection, reliably predicts integral tramadol exposure in critically ill adults and may be useful for assessing CYP2D6 function.
A larger study of the influences of AKI and CYP genotype on hepatic drug metabolism in the critically ill is underway.
Kirwan CJ, et al.: Intensive Care Med. 2009, 35: 1271-1275. 10.1007/s00134-009-1430-7
Kirwan CJ, et al.: Intensive Care Med. 2012, 38: 76-84. 10.1007/s00134-011-2360-8
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Lane, K., Dixon, J., McKeown, D. et al. Using tramadol to monitor hepatic drug metabolism in the critically ill. Crit Care 16, P343 (2012). https://doi.org/10.1186/cc10950
- Acute Kidney Injury
- Critical Care Unit
- Probe Drug
- CYP2D6 Inhibitor